State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (I.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. SUMMARY This research is immediately aimed at designing blood-brain barrier (BBB) permeable magnetic resonance imaging (MRI) contrast agents. The project is directly related to public health since its main objective is to broaden the scope of gadolinium-based contrast agents for the MRI of the brain. MRI contrast agents present distinct advantages in clinical applications and research due to their ability to differentiate between different tissue types. Thus, they offer powerful tools for imaging of cerebral cancers, Alzheimer's disease, as well as conditions associated with brain damage. However, the contrast agents clinically available today can only be used to study conditions involving compromised BBB. Alternatively, they have to be administered invasively, by intracranial injection or by rupturing the BBB. BBB permeable MRI contrast agents will have much broader applications. To achieve BBB permeability, clinically available MRI contrast agents, Omniscan and ProScan will be derivatized with a series of diketopiperizines. The latter have excellent BBB permeability and were previously shown to be capable of acting as molecular shuttles, facilitating transport of highly polar compounds across biological membranes. The proposed contrast agents will be tested in several in vitro assays designed to mimic BBB. They will include parallel artificial membrane permeability assay (PAMPA), immobilized artificial membrane chromatography (lAMC), and bovine brain microvessel endothelial cell (BBMEC) assay. The results gathered from these assays will be compared to the properties of BBB permeable compounds to assess the likelihood of BBB permeability by the proposed contrast agents. Based on the outcome from in vitro testing, candidates will be selected for in vivo experimentation using live rats. BBB permeability will be assayed by performing MRI of the brain of rats previously administered with the proposed contrast agents. PUBLIC HEALTH RELEVANCE: This research is aimed at developing novel tools for magnetic resonance imaging of the brain. These tools will open up new diagnostic frontiers for the MRI of cerebral disorders. From a broad clinical perspective BBB permeable CAs could become valuable tools in planning therapeutic strategy, assessing prognosis and monitoring treatment progress.